Multiple sclerosis (MS) can lead to paralysis and death and affects millions of Americans, often in the prime of their lives. While it is well documented that MS alters vision, hearing, speech and balance, its influence on olfaction - a sense critical for determination of food flavor and protection from spoiled food, leaking natural gas, fire, and other environmental hazards - has been controversial. Indeed, a number of medical textbooks state that the sense of smell is spared in MS, erroneously assuming that the olfactory system is unmyelinated. In 1984, the principal investigator discovered that 23 percent of 31 MS patients scored below normal on the University of Pennsylvania Smell Identification Test (UPSIT). Last year, he reported a series of case studies demonstrating that olfactory dysfunction can be the presenting symptom of MS. In a pilot study of 14 MS patients, the principal investigator has shown a significant relationship between UPSIT scores and the number of plaques within brain regions related to olfactory function (i.e., the orbitofrontal cortex and inferior temporal lobe). No such relationship was observed within non-olfactory related brain regions. These novel findings suggest that the olfactory dysfunction associated with MS directly reflects the degree of neuropathological involvement of central olfactory structures. In the proposed study, the principal investigator will determine the degree to which a number of well-validated olfactory tests are altered in a large cohort of MS patients, including tests of odor detection, identification, discrimination, and memory. He will (1) characterize the olfactory dysfunction of MS on each side of the nose using both psychophysical and electrophysiological measures, (2) determine, using high resolution MRI, whether the test measures are correlated with the number/volume of plaques in olfactory-related structures, (3) establish if olfactory measures are related to the exacerbation or remission of the MS symptoms (including appearance or disappearance of plaques), (4) ascertain whether women are more susceptible than men to MS-related olfactory loss, and (5) establish whether the olfactory test measures are related to neuropsychological measures of cognitive function, with an emphasis on tests which measure orbitofrontal and inferior temporal lobe neural processing. Given the pilot findings of a close relationship between olfactory function and the number of MS-related plaques within olfactory-related structures, the principal investigator expects that this research will explicate, for the first time, the pathogenesis of an olfactory dysfunction associated with a common neurological disorder. Importantly, this study will provide insight as to how different measures of olfactory function are related to pathological alterations within specific central nervous system structures, as well as information for the clinician to rationally counsel patients with MS-related deficits in this underappreciated primary sensory modality.